Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. KDM5A is amplified, overexpressed or translocated in a variety of cancers, including breast cancer, gastric cancer and leukemia. KDM5B is highly expressed in human mammary tumors and breast cancer cell lines, but not in normal breast tissue and genetic knockdown leads to upregulation of tumor suppressor genes, including BRCA1. The goal of this program is to identify and develop selective small molecule inhibitors of KDM5, a family of histone demethylases that are overexpressed in several cancers. During this period, the NCATS group, as part of the KDM5 collaborative team, has worked to develop a large panel of HTS-amenable assays in a number of orthogonal formats, perform primary screening against a number of small molecule libraries, and pursue medicinal chemistry to further refine compound potencies.